tbuckley/cabot-search huggingface dataset:
NIMG-29. ADVANCED MRI BIOMARKERS PREDICT EARLY RESPONSE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA
Authors: Kathleen Schmainda, Melissa Prah, Jennifer Connelly
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Tumor-treating fields (TTFields) is a novel US FDA-approved antimitotic treatment modality for patients with newly diagnosed and recurrent glioblastoma, shown to improve both OS and PFS (Stupp et al 2015). Yet, how to best monitor response to TTfields remains unclear. Conventional (anatomic) MRI is unreliable, often showing initial early radiographic progression followed by tumor regression and clinical benefit, thereby delaying confirmation of response. To address this limitation, we evaluate the utility of quantitative (physiologic) MRI biomarkers. METHODS Patients with newly diagnosed or recurrent IDH wildtype glioblastoma who underwent MRI with DSC-MRI perfusion imaging at 1-2, 3-4 and 5-6 months after TTField treatment were retrospectively identified for this study. Delta T1 (dT1) images were created from standardized (calibrated) pre- and post-contrast T1-weighted images, from which an enhancing lesion volume was objectively determined. Standardized and leakage-corrected relative cerebral blood volume (sRCBV) images were created from the DSC-MRI data. Together, dT1 and sRCBV were used to generate class maps of fractional tumor burden (FTB), which identify highly-vascular and avascular (treatment effect) regions within contrast-enhancement. Kaplan-Meier survival analysis was performed to determine if positive versus negative changes in these metrics, at each time-point relative to pre-treatment values, are predictive of survival. RESULTS 20 patients with newly diagnosed (n=17) or recurrent (n=4) IDH wildtype glioblastoma with a mean TTField compliance of 74.9% were identified. At 1-2 months no metric predicted a survival difference, consistent with the known 4-week delay in tumor stabilization following TTField therapy. At months 3-4 and 5-6 decreasing dT1-determined enhancing volumes showed a survival benefit (p=0.0081, p=0.03). Likewise, a decreasing percentage of highly-vascular tissue, determined from FTB class maps, demonstrated a survival benefit (p=0.0013). CONCLUSIONS Quantitative MRI metrics, including dT1-derived enhancing volumes and FTB/sRCBV-defined regions of high vascularity, demonstrate an ability to provide early indicators of response to TTField treatment.
NIMG-28. DIFFUSION DIFFERENCES IN LOW TO HIGH GRADE GLIOMA TRANSFORMATION
Authors: Michael Flatley, Savannah Duenweg, Allison Lowman, Samuel Bobholz, Margaret Stebbins, Aleksandra Winiarz, Biprojit Nath, Fitzgerald Kyereme, Jennifer Connelly, Dylan Coss, Max Krucoff, Anjishnu Banerjee, Peter LaViolette
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Apparent diffusion coefficient (ADC) maps offer tremendous insight into cellularity and local tissue environment. Proliferation of tumor cells results in increased local cellularity and cell density, thus impairing the free diffusion of water molecules. Therefore, hypointense ADC signals are thought to reflect regions of increased cellularity, and are useful imaging markers for distinguishing neoplastic cellular processes. In this study, we tested the hypothesis that changes in ADC intensity over the course of disease progression differ in progressing gliomas within the tumor-delineated region. METHODS Sixty-three glioma patients from our brain bank were separated into two groups. Group 1 included patients with Grade 1-3 gliomas at surgical diagnosis and progressed to a Grade 4 glioma at autopsy. The second group of patients were those with an initial and final Grade 4 glioma diagnosis. Contrast-enhancing tumor regions on MRI sequences were annotated with an established machine-learning algorithm for each patient on their initial and final MRIs. Average ADC intensity within the contrast enhancing regions was extracted and change in signal intensity between the first and last MRI was calculated for each patient. Finally, the mean intensity difference between Group 2 and Group 1 were evaluated using a linear mixed model. RESULTS We report a negative mean difference between the Group 2 and Group 1s change in ADC intensity over time (p=0.03). CONCLUSIONS These findings suggest changes in cellularity, identified by ADC, are greater in patients who progress from low-to-high grade gliomas. With these results, it may be concluded that change in ADC hypointensity, as a proxy for cellularity, may be a defining imaging characteristic to identify progressing gliomas.
EXTH-44. ENHANCING GLIOBLASTOMA CLEARANCE: EMPOWERING ANTI-EGFRVIII CAR T CELLS WITH A PARACRINE SIRPΓ-DERIVED CD47 BLOCKER
Authors: Tomas Martins, Nazanin Tatari, Deniz Kaymak, Ewelina M Bartoszek, Sabrina Hogan, Alicia Buck, Marie-Françoise Ritz, Ronja Wieboldt, Marta McDaid, Alexandra Gerber, Tala Shekarian, Hayget Mohamed Seid Hedad, Philip Schmassmann, Tobias Weiss, Heinz Laeubli, Gregor Hutter
Journal: Neuro-Oncology (2023)

Abstract A major challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is the immunosuppressive microenvironment (iTME), which is densely populated by protumoral glioma-associated microglia and macrophages (GAMs). Blockade of CD47, a “don’t-eat-me” signal overexpressed by GBM cells, disrupts the CD47-SIRPα axis, and regulates the phagocytic function of GAMs. However, systemic anti-CD47 monotherapy has been ineffective against human solid tumors to date. Here, we combined local CAR T therapy with paracrine GAM modulation to synergistically eliminate GBM. We engineered an armored CAR T cell against EGFRvIII that constitutively secretes a SIRPγ-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eliminated EGFRvIII+ GBM in vitro, and eradicated EGFRvIII-heterogeneous (EGFRvIII+ and EGFRvIII- mosaic) orthotopically xenografted tumors by locoregional application in vivo. This resulted in significant tumor-free long-term survival, followed by partial tumor control upon re-challenge. Combination of anti-CD47 antibodies with anti-EGFRvIII-CAR T cells failed to achieve synergy, pointing towards the importance of sustained paracrine GAM conversion. Paracrine SGRP enhanced CAR T infiltration, tumor clearance and GAM reconversion to an antitumor phenotype as shown by multidimensional brain immunofluorescence microscopy and in-depth spectral flow cytometry multiplexing. Moreover, the plasma of anti-EGFRvIII-SGRP CAR T-treated mice displayed a distinct signature of innate immune activation including TNFα and CCL3. Validation of the anti-EGFRvIII-SGRP CAR T in human explants is ongoing. Furthermore, armoring anti-CD19 CAR T cells with SGRP resulted in superior efficacy in a peripheral lymphoma mouse model compared to anti-CD19 CAR T treatment alone, most problably due to innate immune activation. Thus, local anti-EGFRvIII-SGRP CAR T cell therapy combines the potent antitumor effect of engineered T cells with the modulation of the surrounding innate iTME, inducing a synergistic clearance of GBM in a manner that overcomes known mechanisms of CAR T therapy evasion, such as tumor immune suppression and antigen escape.
STEM-12. TARGETING GLIOBLASTOMA WITH A BRAIN PENETRANT DRUG THAT IMPAIRS BRAIN TUMOUR STEM CELLS
Authors: Arezu Jahani-Asl
Journal: Neuro-Oncology (2023)

Abstract Brain tumour stem cells (BTSCs) are a population of self-renewing malignant stem cells that play an important role in glioblastoma tumour hierarchy and contribute to tumour growth, therapeutic resistance, and tumour relapse. Thus, targeting of BTSCs within the bulk of tumours represents a crucial therapeutic strategy. Here, we report a potent brain penetrant drug (AJ5939) that impairs BTSCs and impedes glioblastoma progression. We show that AJ5939 inhibits the self-renewal and growth of BTSCs harbouring a diverse range of oncogenic mutations without affecting non-oncogenic neural stem cells. Global gene expression profiling revealed significant alterations in BTSC transcriptome and attenuation of the expression of a large panel of genes involved in cell cycle progression, stemness, and DNA repair mechanisms. Mechanistically, we show that AJ5939 impairs Notch signalling pathway via directly targeting this pathway and altering the stemness signature. In combination with ionizing radiation (IR), however, AJ5939 suppresses the DNA repair mechanisms and facilitate the response of the BTSC to ionizing radiation induced cell death. Finally, we present data that AJ5939 treatment of brain tumours in preclinical models significantly prolongs lifespan.
NCOG-08. BEVACIZUMAB ALONE VERSUS BEVACIZUMAB PLUS IRINOTECAN IN PATIENTS WITH RECURRENT GLIOBLASTOMA: A NATIONWIDE POPULATION-BASED STUDY
Authors: Yeonhu Lee, Tae Hoon Roh, Se-Hyuk Kim
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION There is no established treatment for recurrent glioblastoma. For the treatment of recurrent glioblastoma, the antiangiogenic antibody, bevacizumab, is used either alone or in combination with Irinotecan. This study aimed to compare the survival of patients receiving bevacizumab monotherapy (BEV) and those receiving bevacizumab plus irinotecan combination therapy (B+I) in recurrent glioblastoma (GBM), using a nationwide population-based dataset. METHODS Patients matching the ICD code C71.x were screened from the national database. From January 2008 to November 2021, 846 patients who had undergone surgery or biopsy and received concurrent chemoradiotherapy with Temozolomide were included. Of these, 450 received BEV, while 396 received B+I. The patients' demographic characteristics, inpatient stay duration, prescription frequency, and survival outcomes were compared between the two groups. RESULTS The BEV group was older and had a higher percentage of females compared to the B+I group. The survival analysis revealed no significant difference in survival times between the two groups in the univariate and multivariate analysis. Younger age, female gender, and having surgery rather than biopsy were associated with better prognosis. CONCLUSION This study found no significant difference in overall survival between bevacizumab monotherapy and bevacizumab plus irinotecan combination therapy in patients with recurrent GBM. Considering the additional potential toxicity associated with irinotecan, bevacizumab monotherapy may be a suitable treatment option.
NCOG-07. HUB-RELATED GRAPH METRICS AS MARKER FOR COGNITIVE OUTCOMES IN ADULT GLIOMA SURVIVORS AFTER MULTIMODAL THERAPY
Authors: Laurien De Roeck, Jeroen Blommaert, Stefan Sunaert, Patrick Dupont, Paul Clement, Steven De Vleeschouwer, Charlotte Sleurs, Maarten Lambrecht
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Although cognitive impairment is a prevalent long-term side effect in glioma survivors, predictive imaging-based markers remain inconsistent to date. Structural brain network topology could be altered by both the tumor and its’ treatment through reorganization of hubs (i.e. highly interconnected nodes). Here, we explored the role of nodal hub-related graph metrics in cognitive functioning. METHODS 48 WHO grade 2-3 adult glioma survivors ( &amp;gt; 1y post-therapy) and 42 matched controls, underwent a cognitive assessment. Cognitive scores were transformed into w-scores, corrected for age and education. Weighted nodal graph metrics were calculated based on diffusion weighted imaging. Hubs were calculated based on 4 nodal metrics. Significant differences in nodal graph metrics between patients and controls, and hubs versus non-hubs were tested in a repeated measures ANOVA, using Bonferroni correction for multiple testing. Significant group differences in nodal graph metrics were correlated to cognitive scores per domain. RESULTS In controls, 12/78 nodes were defined as hubs. In survivors, the left superior-parietal region and left putamen had a significantly lower likelihood of being a hub (p&amp;lt; .001). These areas showed assortativity to be positively correlated with attention, language and executive function (r(90) &amp;gt; .51,p&amp;lt; .001) and characteristic path length to be negatively correlated with all cognitive domains (r(90) &amp;gt; .51, p&amp;lt; .001). Nodal metrics of clustering coefficient, characteristic path length, local efficiency and assortativity were significantly different between groups in both hub and non-hub regions (p&amp;lt; .001). Except for betweenness centrality, all nodal metrics strongly correlated with cognitive outcomes, occurring more often in hubs (33-50%) than intermediate hubs (10-33%) or non-hubs (4-12%). CONCLUSION Reorganization of hubs is frequently observed in this cohort of glioma survivors. Hub connectivity seems to be important in cognitive functioning, more than for non-hub regions. Therefore, structural nodal hub-related graph metrics might be important in predicting cognitive outcomes.
TMET-08. ELONGATION CONTROL OF MRNA TRANSLATION DRIVES GROUP 3 MEDULLOBLASTOMA ADAPTATION TO NUTRIENT DEPRIVATION
Authors: Alberto Delaidelli, Betty Yao, Fares Burwag, Jessica Oliveira de Santis, Yue Zhou Huang, Haifeng Zhang, Gian Luca Negri, Christopher Hughes, Gabriel Leprivier, Poul Sorensen
Journal: Neuro-Oncology (2023)

Abstract Group 3 affiliation and MYC genetic amplification are associated with poor life expectancy and substantial morbidity in children suffering from medulloblastoma (MB). However, the high metabolic demand induced by MYC-driven transformation sensitizes MYC-overexpressing MB to cell death under conditions of nutrient deprivation (ND). Additionally, MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, promotes survival of MYC-overexpressing tumors under ND. Interestingly, eEF2K is overexpressed in MYC-driven MB and our preliminary proteomics data highlight large-scale alterations in OXPHOS components affecting eEF2K deficient MB cells. We therefore hypothesized that eEF2K activity is required for the selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MB. We performed Multiplexed enhanced Protein Dynamic Mass Spectrometry in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. Messenger RNAs encoding multiple (9 out of 10 detected) components of the mitochondrial OXPHOS pathway are selectively translated upon eEF2K activation. Inactivation of eEF2K by genetic KO leads to the disassembly of electron transport chain (ETC) complexes I-IV without affecting mRNA levels of their respective components. Consistently, eEF2K KO MB cells display decreased mitochondrial membrane potential and 20% increased proton leak thorough the mitochondrial membrane. In addition, eEF2K inactivation results in increased Group 3 MB cell death under ND and doubles survival of MB bearing mice fed with calorie restricted diets (p&amp;lt; 0.05). Control of mRNA translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MB, likely representing an adaptive response by which MYC-driven MB cells cope with acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs as eEF2K activity appears critical under metabolic stress conditions.
NCMP-06. INTRAMEDULLARY SPINAL CORD METASTASIS OF RENAL CELL CARCINOMA: A COMPARISON OF CASES AND TREATMENT OUTCOMES
Authors: Corinna Fukushima, Timothy Kuzel
Journal: Neuro-Oncology (2023)

Abstract Renal cell carcinoma (RCC) intramedullary spinal cord metastasis (ISCM) is a rare but frequently devastating diagnosis. Due to its rarity, there is currently no clear standard of care for RCC ISCM management. However, with improvements in metastatic RCC management and imaging for early detection of ISCM, we may see a rise in the incidence of RCC patients developing ISCM, for which treatment guidelines are lacking. Here, we aim to add to the growing body of RCC ISCM literature with two cases- one with ISCM managed with surgery, radiation, and immunotherapy, and the other managed with only radiation, immunotherapy, and chemotherapy. Case 1 is a 47 year old male with RCC and lung and bone metastases who underwent nephrectomy, lobectomy, high dose IL-2 therapy, and immunotherapy. He later developed worsening low back pain, and lower extremity paresthesias and weakness. Imaging revealed a thoracic metastasis for which he was started on steroids, underwent surgical resection followed by radiation therapy, and immunotherapy. Serial imaging and clinical exams have not found evidence of ISCM recurrence 5 years after initial resection. Case 2 is a 74 year old female with RCC with cerebellar metastasis who underwent nephrectomy, suboccipital craniotomy with mass resection, radiation therapy, and immunotherapy. 3 years later, she developed neck pain with right arm paresthesias, and imaging revealed cervical spine ISCM. Patient declined surgical intervention, and she was managed with steroids and radiation therapy, followed by chemotherapy. Approximately 5 years after initial ISCM findings, serial imaging and clinical exams have not revealed evidence of disease progression. These cases have several important differences including prior central nervous system metastases, ISCM location, and surgical intervention. However, both have not shown evidence of disease progression at similar time points. We hope these cases add to the small body of cases to move towards developing treatment guidelines.
TMIC-57. CHARTING THE SPATIAL ARCHITECTURE OF GLIOBLASTOMA USING GBMAP: INSIGHTS FROM IN SITU SEQUENCING
Authors: Cristian Ruiz, Sergio Marco-Salas, Erik Samuelsson, Marco Grillo, Sebastian Brandner, Ananya Roy, Karin Forsberg-Nilsson, Mariëtte Kranendonk, Mats Nilsson, Hendrik Stunnenberg
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GB), an aggressive brain malignancy, is associated with poor prognosis and quality of life. Single-cell RNA sequencing has helped unravel the complexity of GB cell states. However, to comprehensively unravel the pathobiology of GB, it is essential to consider the spatial context in which these cells reside within the tumor microenvironment (TME). In this study, we aimed to understand the spatial architecture of GB tumors and its implications on cellular and molecular heterogeneity. To achieve this, we developed GBmap, a comprehensive resource that harmonizes 26 datasets comprising 239 patients and over 1.1 million cells. Leveraging computational advancements, we utilized GBmap to create a GB-specific panel for charting the spatial architecture of tumors using an in situ sequencing (ISS)-based platform (HybISS) in an independent cohort of 13 tumors. We curated a panel of 209 genes based on the GBmap, capturing cell phenotypic features, intra- and inter-tissue heterogeneity, and in silico L-R analysis predictions. The panel includes markers for specific cellular processes such as inflammation, extracellular matrix remodeling, hypoxia, and angiogenesis, providing an additional layer of functional information. Our optimized pipeline incorporates a new method for ISS-based transcriptomics data (direct RNA targeting), which enhances sensitivity and tolerance for tissue specimens of poorer RNA quality. This new approach enables improved cell type/state resolution and classification confidence. Using this advanced approach, we observed heterogeneous cell-cell colocalization patterns that vary among patients, revealing spatiotemporal distributions of specific cancer phenotypes and distinct co-localization patterns with neighboring cells in the TME. Our findings showcase the unprecedented spatial and cellular resolution achieved, surpassing previous GB studies. Our study sheds light on the spatial architecture of GB tumors, unveiling previously unexplored cellular and molecular interactions. GBmap and our optimized pipeline offer a powerful resource for researchers to investigate GB heterogeneity, generate hypotheses, and contribute to advancing GB research.
INNV-32. RELIABILITY OF SERIAL NEUROPATHOLOGICAL ASSESSMENT TO DIFFERENTIATE TUMOR PROGRESSION FROM PSEUDO-PROGRESSION IN GLIOMA
Authors: Lara Khoury, William Harrison, Shakti Ramkissoon, Kimberly Stogner-Underwood, Ryan T Mott, James Miller, Glenn Lesser, Michael Chan, Christina Cramer, Steven Tatter, Adrian Laxton, Jaclyn White, Thomas Tavolara, Fang-Chi Hsu, Roy Strowd
Journal: Neuro-Oncology (2023)

Abstract Histopathology is the gold standard for distinguishing tumor recurrence from treatment-induced necrosis but differentiating pseudoprogression from true recurrence is challenging in tumors with ambiguous morphological features. Prior research reported a 36% inter-rater agreement during suspected recurrence (Holdhoff et al., 2019). While serial radiographic and laboratory assessments are common, serial histopathological assessments are not. This study evaluated agreement and factors influencing assessment of active and inactive tumors through single and multiple time-point histopathological assessments. Patients who underwent initial and subsequent reoperation were identified, and their available histology slides were examined retrospectively. Four independent neuropathologists conducted two types of reviews: single time-point reviews using most recent biopsy/surgery slides, and multiple time-point reviews comparing images from initial and repeat biopsies taken 1-3 months apart. Neuropathologists completed a questionnaire assessing various tumor characteristics. Assignments were categorized as "active tumor," "treatment effect," or "unable to classify." 324 assessments were conducted (108 single time-point, 216 multiple time-point). Intraclass correlation coefficients for single vs. multiple time-point assessments were 0.72-0.93 for active tumors and 0.57-0.86 for inactive tumors. Pathologists' assessment of % inactive tumor was influenced by mitotic activity (p= 0.0028), cellularity (p&amp;lt; 0.0001), hyalinized vessels (p= 0.0019), and necrosis (p= 0.0046). Evaluation of % active tumor was influenced by hyalinized vessels (p= 0.0006), mitotic activity (p&amp;lt; 0.0001), cellularity (p&amp;lt; 0.0001), and microvascular proliferation (p= 0.0093), with the latter three factors specifically affecting final sign-out pathology. Serial histopathological assessment didn’t affect determination of % active or inactive tumor. No association between % inactive tumor and fibrinoid necrosis for single time-point (p= 0.34) but a strong negative association was seen for serial assessment (p= 0.0006). Inter-rater agreement was higher for identifying active tumors than inactive tumors in both case reviews. Changes in necrosis between tissue samples in single vs. multiple timepoint assessments influenced pathologists' assessment of % inactive tumor.